Process Line and Process Facility Qualification
Process line and process facility qualification (e.g. Sterile Fill Line Equipment) for sterile pharmaceutical manufacturing is one of the most critical assets. For aseptic manufacturing in compliance with cGMP, EU GMP Guide Annex 1, FDA guidance, and ISO 14644 principles are applicable.
Regulation and Requirements for Qualification Processes
Objective of Qualification Regulation
The objective of qualification and validation of process equipment, process facilities, or analytical instruments is the demonstration of fitness for purpose for its intended use. To ensure that products meet their specifications, a diverse repertoire of analytical instruments, process equipment and utilities for the production and quality control of biopharmaceuticals is necessary.
Statutory and regulatory requirements of GMP
The legal basis for USA Good Manufacturing Practices (GMP) is primarily the Federal Food, Drug, and Cosmetic Act (FD&C Act). The FD&C Act authorizes the FDA to establish mandatory standards and principles for manufacturing, processing, packing and product holding. These regulations are legally codified of the CFR (Code of Federal Regulations) Title 21 Food and Drugs parts 210 and 211.
Food, Drug, and Cosmetic Act (FD&C Act) Section 501(B)
A drug is deemed adulterated if its manufacturing, processing, packing, or holding method do not conform to cGMP to ensure safety, quality, and purity.
(a) Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act provides that a drug (including a drug contained in a medicated feed) shall be deemed to be adulterated if the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirement of the act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.
Qualification Phases
Qualification is a multilevel process consisting of four main qualification phases: DQ, IQ, OQ, and PQ
Design Qualification (DQ)
The Design Qualification (DQ) verifies the functional and operational specifications through documented activities and that the specified design of the process equipment, process facility, instrument or device is suitable for the intended purpose.
The selection and purchase of a new instrument, process equipment, or process facility shall follow a documented decision process. The decision is based on the needs related to the intended purpose..
The main DQ phases include:
I Planning
- Design stage
- URS, FS
- System Classification
- Risk Assessment
II Procurement
III Suppliers Work
- FAT
- SAT
Installation Qualification (IQ)
Definition
The Installation Qualification (IQ) verifies through documented activities that the process equipment is delivered as designed and specified, according to the URS and that the equipment is properly installed and assembled in the designated environment.
Objective
The IQ verifies the correct implementation of the requirements defined in the design qualification (DQ) during the assembly and installation of the system or equipment. The verification of the installation qualification (IQ) is basically carried out on the basis of the previously devised URS.
General IQ requirements
- Conformity checks with order (instrument, material, documentation)
- Check for damage
- Check for required medial supply (connections, environmental conditions)
- Check of correct instrument installation and assembly
General IQ activities
- Instrument delivery
- Description
- Utilities/Facility/Environment
- Assembly and installation
- Software installation, network, and data storage
- Installation verification
Operational Qualification (OQ)
The Operational Qualification (OQ) verifies through documented activities that the process equipment, process facility, or analytical instrument operates within its predetermined specifications and acceptance criteria as designed and installed.
- OQ follows the IQ
- The basis for operational qualification activities is the risk assessment, which considers critical quality attributes (CQAs) and critical process parameters (CPPs).
- FAT and SAT should be incorporated into testing activities to avoid retesting.
Performance Qualification (PQ)
Definition
The Performance Qualification (PQ) verifies through documented activities that the process equipment, process facility, or analytical instrument operates consistently and reproducibly within predefined process specifications and acceptance criteria under actual conditions of use. PQ therefore verifies the fitness for purpose of the process equipment or process facility under actual conditions of use.
URS
Specifications describe the customer’s requirements for process equipment, process facilities, or analytical instruments. Specifications, including validation parameters with their acceptance criteria, are the basis for the entire product life cycle of a process equipment or process facility.
General instructions of URS
- Description of the analysis, test method, system
- Description of the intended use of the equipment
- Description of functional specification
- Description of performance specification
- Description of environmental specification
- Safety aspects
Risk Assessment
The risk assessment identifies and provides scientific knowledge about potential quality risks. The impact of these potential risks on quality and safety will then be analyzed and assessed.
System Classification
To determine the extent of qualification operations the systems are classified in categories depending on their complicity and the criticality on its intended use.
Group A includes the simplest standards devices and instruments such as magnetic stirrer or vortex mixer which are used without measurement capability. Their handling is simple and self-explanatory. The quality of product and process will not be affected by this category and therefore qualification activities require only the basics.
Group B includes instruments which are more complex and provide a measurement capability or a condition that may affect a measurement, for example a pH meter and oven or incubator. These instruments may have firmware but are not software-controlled. The extend of qualification activities depends on criticality regarding critical quality attributes (CQA) and critical process parameters (CPP) which is to be analyzed by a risk assessment.
Group C includes complex analytical instruments with software-controlled measurements and analysis such as HPLC, mass spectrometer or flow cytometer. This category requires the highest quality standards. Their qualification is demanding and labor-intensive. It also includes the computerized software validation (CSV) which is even more elaborate and demanding.
Instrument Calibration
Calibration is a test procedure for determining the output and input variables, i.e. the measured value and the corresponding true or correct value using a reference standard to determine the deviation of a test device (e.g. test instrument or analytical instrument).
FAT
For complex process line or process facilities the framework is extended to include functional specifications (FS) and factory acceptance testing (FAT). FAT is performed by and at the vendor’s location. The primary objective is to ensure that the system meets the functional and operational specifications as devised in the URS and DQ. FAT may include all activities from commissioning to qualification (DQ, IQ, OQ). FAT should be incorporated into the qualification operations where possible.
SAT
Site acceptance testing (SAT) includes analytical instrument installation, process equipment installation and start-up which are normally undertaken in IQ and OQ. The equipment is retested when installed at the manufacturing site by the vendor. Some of the SAT activities may be satisfied and do not need to be repeated by the manufacturer. The documentation can be incorporated into the qualification process.
Specifications and acceptance criteria
Within a risk assessment, the system is classified. This classification essentially determines the extend of requirements to be qualified. Each laboratory is responsible for setting and justify the specifications and acceptance criteria itself.
- Specification and validation parameters represent the core element of any qualification or validation plan.
- Specifications, validation parameters and their acceptance criteria must be established before qualification or validation is carried out.
- When establishing validation parameters and acceptance criteria, expertise from drug development, drug manufacturing and else expertise should be incorporated into validation and qualification operations.
Summary
Qualification and validation activities are part of good manufacturing practice (GMP). The use of qualified instruments and process equipment is mandatory because it is required by regulatory authorities. It contributes to customers’ confidence that the instruments and equipment perform suitably according to their intended purpose.
Qualification and validation operations require compliance with predefined specifications and GMP regulations to ensure the quality and reliability of manufacturing processes with regard to the quality, safety and efficacy of medicinal products.
For GMP-related environments such as pharmaceutical, biotechnology, and treatment centers for ATMPs, qualification and validation are therefore central GMP requirements for GMP compliance.
